Enhancing Membrane Repair Using Recombinant MG53/TRIM72 (rhMG53) Reduces Neurotoxicity in Alzheimer's Disease Models.

Abstract

Alzheimer's Disease (AD) is the most common neurodegenerative disease that involves neuronal cell death initiated by the breakdown of the plasma membrane. Amyloid beta (Aβ), a hallmark protein that contributes to AD pathogenesis, is known to interact directly with the plasma membrane and induce increased intracellular calcium levels, reactive oxygen species (ROS), and cell death. Our recent studies revealed that elevated levels of Aβ₄₂ induce a plasma membrane repair defect in neurons that compromises this conserved cellular response that would normally repair the disruption. Here, we tested if recombinant MG53/TRIM72 protein (rhMG53), a therapeutic protein known to increase plasma membrane repair capacity, could enhance membrane repair in AD neurons. rhMG53 increased plasma membrane repair in ex vivo and in vitro tissue treated with Aβ₄₂ or cerebrospinal fluid from AD patients, normalizing intracellular calcium levels, ROS, and cell death in treated cells. This study demonstrates that increasing plasma membrane repair can rescue neural cells from the neurotoxic effects of Aβ, indicating that elevating plasma membrane repair could be a viable therapeutic approach to reduce neuronal death in AD.